A Decade Of Discovery Yields a Shock About the Brain

Published: January 4, 2000

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These researchers identified a zone within two hollow cavities of the rat brain, called ventricles, where new cells are born and then migrate to the brain's interior. The zone contains so-called stem cells that give rise to many other cell types, including neurons and glial cells that nourish neurons.

The new cells seen in the rat brains appear at a higher rate after challenges like intense training, injury or an infection, Dr. Raastad said. Within a few years, researchers found the cells in adult mice, guinea pigs, rabbits and monkeys. In the mid-1980's, other researchers found irrefutable evidence that new cells were born in the brains of adult canaries learning new songs and chickadees that were remembering where they had stashed their winter seeds. But researchers still did not believe that new cells were created in human brains, Dr. Raastad said.

In 1997, Dr. Elizabeth Gould, an assistant professor of neuroscience at Princeton, and colleagues showed that neurogenesis, or the birth of new cells, occurred in the hippocampuses of tree shrews and marmoset monkeys. But Dr. Rakic and others said this was not possible in humans.

In 1998, Dr. Gage demonstrated that the number of brain cells in the hippocampuses of mice raised in stimulating environments increased by 15 percent -- and that the cells were born in the ventricle zone.

''This made us go look for the same in humans,'' Dr. Gage said. Swedish colleagues were using a special substance that integrates into the DNA of dividing cells to track tumor cells in cancer patients, he said. Last year, this substance was found in the hippocampuses of five cancer patients whose brains were dissected immediately after they died.

This was a ''thrilling'' discovery, Dr. Gage said. It means that the human brain makes new cells in an area already known to be involved in short-term memory. Some sort of neurogenesis may be widespread in the brain and spinal cord for maintenance, he said. Like skin, the brain may be repairing itself all the time. But like a big gash to the skin, a large brain injury like a stroke can overwhelm the repair system.

As for the rest of the brain, including the cortex, where complex functions like language and long-term memories reside, Dr. Gould injected the same dye used in the human experiments into macaque monkey brains. By tracing the chemical, she found that neurons had been born in the ventricles and had migrated into the higher cortex, where they made new axons. They appeared to connect up to local circuitry and perhaps extend into wider circuits, she said, adding that the same might be true for human brains.

But the most surprising finding about new cell growth in the human brain has been virtually ignored by most neuroscientists. This part of the story began more than two decades ago when a young doctor in training, William Rodman Shankle, salvaged a stack of cardboard boxes containing the largest database ever collected on the developing human cerebral cortex. The data had been collected from 1939 to 1967 by Dr. Jesse L. Conel of Boston Children's Hospital, who examined the brains of infants and children up to age 6 who had died from accidents or diseases not affecting brain cells. Before his death, he made more than four million measurements, including the width, thickness and packing density of brain cells at birth and at 1, 3, 6, 15, 24, 48 and 72 months of age.

Dr. Conel published eight volumes of research. Several boxes of his raw data were about to be thrown out -- tissue samples and slides already having been discarded -- when Dr. Shankle, now a neurologist at the University of California at Irvine, noticed them stacked in a hallway at Boston University and rescued them.

Dr. Conel did not have computer tools to measure exact numbers of cells, Dr. Shankle said, but he did describe, at each age and within 35 brain areas, the appearance of vertical columns of neurons. It is now known that higher brain functions stem from arrays of these columns.

Dr. Shankle and his colleagues re-examined Dr. Conel's data using modern mathematical and computer techniques to allow for cell shrinkage and to distinguish neurons from other kinds of brain cells. They found an astonishingly dynamic pattern in all 35 areas. In each square millimeter of tissue, Dr. Shankle said, the number of neurons rises by a third from birth to 3 months as new cells are added. Then the number plummets back to birth level between 3 and 15 months. After this point, the number increases rapidly, doubling by the age of 6 years. It probably continues increasing, although at a slower rate, up to age 18 or 21, Dr. Shankle said.

The brain enlarges by making new columns, not by making existing ones larger, Dr. Shankle said. ''I suspect that a single set of rules constructs all brains,'' he said. ''Children progress through the same stage of development at the same rates independent of their culture.''

This rapid growth and construction of brain tissue may help explain why children whose left or right brain hemispheres are removed entirely seem to develop more or less normally, Dr. Shankle said. The rate of growth, or plasticity, is so large early on, they can learn to do most things with their remaining brain tissue.

Dr. Anderson said that Dr. Shankle's findings were ''well described and adequately analyzed,'' and concluded, ''I see no major flaws in his handling of the material.''

But Dr. William T. Greenough, a University of Illinois neuroscientist, said he was not yet convinced that Dr. Shankle had proved that the growth was from new nerve cells and not from supporting cells called glia. ''He may be right,'' he said, ''but the work needs to be replicated.''

Meanwhile, Dr. Steven A. Goldman of Cornell Medical Center in New York City is studying human brain tissue removed from epilepsy patients and has found progenitor cells in the ventricles. About 10 percent of cells in this zone are progenitors that give rise to other cell types, he said. This is a trivial number compared with the brain's 100 billion cells, but it may be enough to carry out maintenance and repair of the higher cortex, he said.

The challenge is to make such cells useful, Dr. Goldman said. ''We still don't know where they go,'' he said, ''but we do know they're dividing. Some are becoming neurons.'' If ways could be found to induce their expansion in the human brain, he said, new treatments for a wide variety of brain disorders would be on the near horizon.

Chart/Diagram: ''A Work in Progress'' Scientists are discovering new evidence that the number of neurons in the brain, thought to be fixed, changes throughout life. Analyzing data collected decades ago, brain researchers have been able to estimate the number of neurons in areas of the cerebral cortex at various stages of life. The number of neurons rises for the first three months of life, then falls as connections are pruned, then rises sharply until about age 6. Some evidence suggests new neurons are formed well into adulthood. (Sources: Dr. William R. Shankle, Dr. James H. Fallon, Dr. Junko Hara, University of California at Irvine; Dr. Benjamin H. Landing, University of Southern California, American Medical Association Encyclopedia of Medicine)(pg. F4)